|De Los Santos, Teresa|
Submitted to: American Society for Virology Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 4/1/2005
Publication Date: 6/18/2005
Citation: De Los Santos, T., Botton, S.D., Grubman, M.J. 2005. The Leader Proteinase of Foot-and-Mouth Disease Virus Inhibits the Induction of Interferon Beta mRNA and Blocks the Host Innate Immune Response. American Society for Virology 24th Annual Meeting. P. W3-2. Interpretive Summary:
Technical Abstract: Foot-and-mouth disease virus (FMDV) is a highly contagious pathogen of cloven hoofed animals that causes an economically devastating disease. We have previously shown that the virulence of FMDV correlates with the presence of the viral gene product Lpro (leader), a papain-like proteinase responsible for the shut off of host protein synthesis. Lpro cleaves the translation initiation factor eIF-4G resulting in the inhibition of cap-dependent mRNA translation while viral IRES-dependent mRNA translation remains unaffected. Viruses lacking Lpro (LLV2) are attenuated in cell culture and in the animal host, including cattle and swine. LLV2 is able to infect and replicate in primary and secondary cells, but in contrast to wild type (WT) virus does not form plaques in these cells. The inability to form plaques is associated with an increased level of antiviral activity in the supernatant of the LLV2-infected cells. To understand the molecular basis of this response we have measured the levels of mRNA for IFN beta and some IFN induced genes genes in SK6 cells, a cell line that behaves similarly to primary or secondary porcine kidney (PK) cell cultures upon infection with FMDV. By real-time RT-PCR we observed that LLV2 is a more efficient inducer of IFN beta mRNA expression, 15-20 fold higher levels, than WT virus. The induction of IFN beta correlates with increased levels of RNA-dependent protein kinase (PKR), 2'-5' oligoadenylate synthetase (OAS) and Mx1 mRNAs as well as an increase in antiviral activity. Inhibition of PKR expression, by RNAi, resulted in higher virus yield indicating a direct role of this gene in the antiviral response to FMDV in porcine cells. The observation that Lpro reduces the viral-triggered induction of IFN beta mRNA expression suggests an additional novel function for this protein in antagonizing the innate immune response. Currently we are examining the mechanism involved in this regulation.